Abstract: Lung diseases are among the most common medical conditions worldwide. A hallmark of many lung diseases is aberrant polarity of the lung epithelium; disrupted lung epithelial cell architecture has been observed in several diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis. Healthy luminal cells in the airways of the lung exhibit distinct apical-basal polarity, and a major regulator of cell polarity is the Crumbs complex, which is organized by the transmembrane Crumbs proteins. Our preliminary data has shown that loss of Crumbs3 (Crb3), the isoform predominantly expressed in the lung, in the luminal cells of the airway epithelium in adult mice leads to dramatic cell fate defects. These airways form lesions of stratified cells that express markers of basal cells, which are stem cells of the lung airway epithelium that normally act to repair damage. Using lineage tracing, our data suggest that conditional deletion of Crb3 results in both de-differentiation and non-cell-autonomous signaling that leads to basal cell expansion. We have also demonstrated that combined deletion of Yap and Taz, the transcriptional effectors of the Hippo pathway, is sufficient to revert the formation of these lesions. Our preliminary RNA-seq profiling of lung epithelial cells has revealed neuregulin-1 (Nrg1) as a transcriptional target of Yap/Taz. This is in accordance with our mouse model, which shows increased levels of Nrg1 mRNA in Crb3-deleted lesions. Nrg1 is classically an activator of the ErbB family of membrane receptors, but there is also evidence suggesting it activates Yap transcriptional activity. Our goals are to: 1) define the regulatory relationship between Yap/Taz and Nrg1/ErbB signaling in promoting the growth of basal airway epithelial cells; and 2) determine the importance of Nrg1/ErbB and its downstream signaling in the formation and maintenance of Crb3-null basal cell lesions in vivo. Collectively, our proposed studies will provide important insight into the signaling events downstream of defective cell polarity, which will improve our understanding of the variety of lung diseases in which it is implicated.